Method of encapsulating an active substance

ABSTRACT

The invention provides a method of encapsulating an active substance in an interpolymer complex, to make an encapsulated product in particulate form. The method comprises forming a mixture of a supercritical fluid, an interpolymer complex and an active substance and then causing or allowing the interpolymer complex to encapsulate the active substance. The encapsulated product is then separated from the supercritical fluid and, if necessary, the product is subjected to size reduction to ontain particles in which the active substance is encapsulated by the interpolymer complex.

This invention relates to a method of encapsulating an active substancein an interpolymer complex to make an encapsulated product inparticulate form. It also relates to such product, when made by themethod.

According to the invention there is provided a method of encapsulatingan active substance in a polymeric encapsulating material to make anencapsulated product in particulate form by forming a mixture of asupercritical fluid, a polymeric encapsulating material and an activesubstance, causing or allowing the encapsulating material to encapsulatethe active substance to form an encapsulated product, separating theencapsulated product from the supercritical fluid and, if necessary,subjecting the encapsulated product to size reduction to obtainencapsulated product particles in which the active substance isencapsulated by the encapsulating material, the forming of the mixturebeing of the supercritical fluid, the active substance and a polymericencapsulating material in the form of an interpolymer complex, so thatthe encapsulated product comprises particles of the active substanceencapsulated by the interpolymer complex.

The forming of the mixture may comprise the step of dissolving apre-prepared interpolymer complex in the supercritical fluid so that themixture comprises a solution of the interpolymer complex as solute inthe supercritical fluid as solvent.

Instead, the forming of the mixture may comprise the steps of dissolvingin the supercritical fluid each of at least two complementary polymerscapable of interacting together in solution in a supercritical fluid toform an interpolymer complex, to form a solution in which they aresolutes and the supercritical solution is a solvent, and causing orallowing the complementary polymers to interact together to form theinterpolymer complex in the supercritical fluid. In this case, if thecomplementary polymers interact together to form an interpolymer complexwhich is soluble in the supercritical fluid, the forming of the mixturemay comprise the step of dissolving each of the complementary polymersin the supercritical fluid to form a solution in which the complementarypolymers respectively form solutes in the supercritical fluid assolvent, the causing or allowing of the complementary polymers tointeract together acting to form the interpolymer complex as solutedissolved in the supercritical fluid as solvent. Instead, if thecomplementary polymers interact together to form an interpolymer complexwhich is insoluble in the supercritical fluid, the forming of themixture may comprise the steps of separately dissolving each of thecomplementary polymers in the supercritical fluid to form separatesolutions in which the complementary polymers respectively form solutesin the supercritical fluid as solvent, and mixing the separate solutionstogether to cause or allow the complementary polymers to interacttogether to form the interpolymer complex, the forming of theinterpolymer complex resulting in precipitation thereof from thesupercritical fluid. In each case, the forming of the mixture mayinclude the step of admixing a solubilizing agent into the mixture, thesolubilizing agent acting to facilitate dissolving in the supercriticalfluid of at least one member of the group consisting of thecomplementary polymers and the interpolymer complex. Examples of suchsolubilizing agents are entraining agents such as low molecular weightsolvents, for example, low molecular weight alcohols, with molecularweights below 100 g/mol, which are easily soluble in the supercriticalfluid and assist dissolution therein of the complementary polymersand/or of the interpolymer complex. Furthermore the forming of themixture may comprise dispersing the active substance as a suspension ofparticles in the supercritical fluid, the causing or allowing of theinterpolymer complex to encapsulate the particles of the activesubstance being by causing or allowing the interpolymer complex toprecipitate from the supercritical fluid on to the surfaces of theparticles.

When the interpolymer complex is soluble in the supercritical fluid andremains dissolved therein after formation thereof, the forming of themixture of the interpolymer complex, the supercritical fluid and theactive substance may include dissolving each of at least twocomplementary polymers capable of interacting together in solution toform an interpolymer complex, simultaneously in the same supercriticalfluid, or separately to form separate complementary polymer solutions,and mixing the separate solutions together to allow the complementarypolymers therein to interact to form the polymer complex in solution inthe supercritical fluid. The active substance may be dispersed in atleast one of the complementary solutions, before the associated polymeris dissolved therein. Instead, or in addition, the active substance maybe dispersed in one of the complementary polymer solutions, afterformation of the solution by dissolving its polymer in its supercriticalfluid. A further possibility is that, instead or in addition, the activesubstance may be dispersed in the interpolymer complex solution, afterthe mixing of any complementary polymer solutions has taken place andafter the complementary polymers have interacted to form theinterpolymer complex, but before the precipitation of the interpolymercomplex. In cases where the solubility of the interpolymer complex islow and the interpolymer complex is formed in the supercritical fluid athigh concentrations above its saturation concentration, it may beallowed to precipitate spontaneously on to particles of the activesubstance as soon as the interpolymer complex is formed.

When the interpolymer complex is pre-prepared, it may be pre-preparedfor example as described in the Applicant's U.S. Pat. No. 6,221,399,followed by dissolving the interpolymer complex as a solute in thesupercritical fluid. In this case the active substance may be dispersedin the supercritical fluid before the interpolymer complex is dissolvedtherein, and/or the active substance may be dispersed in the solution,after the interpolymer complex has been dissolved in the supercriticalfluid.

Causing the interpolymer complex to precipitate from the solution on tothe active substance may be by any suitable method. Thus, the pressureof the supercritical fluid solvent may be altered to cause theprecipitation. Similarly, the temperature of the solvent may be alteredto cause the precipitation and, if desired, both pressure andtemperature may be altered to cause the precipitation. Instead, or inaddition, a non-solvent constituent, which causes the precipitation, maybe added to the solution. A further possibility is that the solution ofinterpolymer complex with the active substance dispersed therein can beconcentrated by allowing the solvent to evaporate, e.g. by atomizing thesolution, for example in the fashion of spray drying, to produce anencapsulated product. When the active substance is a porous particulatesolid the method may include precipitating the interpolymer complex onto both the outer surfaces of the particles of active substance, and onto the inner surfaces of their porous interiors.

As indicated above, forming the solution or solutions may include theuse of a suitable solubilizing agent for facilitating the dissolution ofone or more of the complementary polymers and/or the interpolymercomplex in the supercritical fluid solvent. In this regard thesupercritical fluid solvent may be a single substance or may be amixture of a plurality of substances, i.e. a mixture of two or moredifferent molecular species, and the method may comprise using more thanone such solubilizing agent.

The interpolymer complexes of the present invention may be formed by theinteraction, by interpolymer complexation, between two or more polymersby hydrogen bonding, by ionic forces, by van der Waal's forces, byhydrophobic interactions and/or by electrostatic forces, as describedmore fully in the Applicant's abovementioned U.S. Pat. No. 6,221,399.

The forming of the mixture may comprise, in another embodiment of theinvention, the step of dissolving the active substance as solute in thesupercritical fluid as solvent to form a solution of the activesubstance in the supercritical fluid, the causing or allowing of theinterpolymer complex to encapsulate the active substance comprisingatomizing the mixture in an atmosphere having a temperature and pressuresuch that the supercritical fluid solvent evaporates to leave a residuecomprising particles in which the active substance is encapsulated bythe interpolymer complex.

In this context the word evaporate naturally does not have its usualmeaning of leaving the liquid state and entering the gaseous state butmeans, instead, that it leaves, the supercritical state and enters asubcritical state in which either the temperature is below the criticaltemperature, or the pressure is below the critical pressure, or both.

A further possibility is that the forming of the mixture may comprisethe step of dissolving the supercritical fluid in the interpolymercomplex to liquefy or plasticise the interpolymer complex. In this case,the forming of the mixture may comprise the steps of blending at leasttwo complementary polymers, capable of interacting together when blendedand in liquefied or plasticised form, to obtain a blend comprising thepolymers, dissolving the supercritical fluid in the polymers, andcausing or allowing the polymers to interact together in blendedliquefied or plasticised form to form the interpolymer complex. Theblending of the polymers may be to form a particle blend comprisingpolymer particles having a particle size of at most 1000 μm, preferablyat most 500 μm and more preferably at most 300 μm, after which thesupercritical fluid is dissolved in the polymer particles. Instead, thesupercritical fluid may be separately dissolved in the complementarypolymers in particle form comprising particles having a particle size ofat most 1000 μm, preferably at most 500 μm and more preferably at most300 μm, after which the polymers in liquefied or plasticised form areblended to form the blend. The causing or allowing of the interpolymercomplex to encapsulate the active substance may comprise atomizing themixture in an atmosphere having a temperature and pressure such that thesupercritical fluid evaporates to leave a residue comprising particlesin which the active substance is encapsulated by the interpolymercomplex. In this case, the dissolving of the supercritical fluid in theinterpolymer complex to liquefy or plasticise the interpolymer complexmay include the step of dispersing a viscosity-reducing agent in theinterpolymer complex to reduce the viscosity of the interpolymer complexto facilitate the atomizing. Thus, for example, poly(ethylene glycol)may be dissolved as a viscosity reducing agent to reduce the viscosityof the liquefied or plasticised interpolymer complex. Instead, thecausing or allowing of the interpolymer complex to encapsulate theactive substance may comprise allowing the supercritical fluid toevaporate to leave a solid residue comprising the active substancedispersed in the interpolymer complex, and subjecting the residue tosize reduction to obtain particles in which the active substance isencapsulated by the interpolymer complex.

In general, the forming of the mixture may include the step of admixinga polymer surfactant into the mixture, for example a so-called poloxameror poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide)tri-block copolymers, to enhance the interaction between thecomplementary polymers and/or to enhance the solubility of thesupercritical fluid in the complementary polymers and in theinterpolymer complex. Such polymeric surfactant is usually easilyliquefiable by the supercritical fluid and helps the supercritical fluidto liquefy the complementary polymers and the interpolymer complex.However, when the surfactant is soluble in the supercritical fluid, itenhances dissolution of the complementary polymers and interpolymercomplex in the supercritical fluid rather than liquefaction thereof bythe supercritical fluid.

It should be noted that, particularly when the interpolymer complexencapsulating the active substance in the encapsulation product isinsoluble and neither liquefiable nor plasticisable in the supercriticalfluid in which the complementary polymers interact to form theinterpolymer complex, the encapsulation method of the present inventionmay be carried out more than once, the second and each subsequentencapsulation being carried out on an active substance which iscontained in the encapsulated product of the previous encapsulation.

In other words, if desired, the encapsulation method of the presentinvention may be repeated more than once, the second and each subsequentencapsulation being carried out on an active substance which is providedby the encapsulated product of the previous encapsulation.

The polymers which form the interpolymer complex by interpolymercomplexation may be selected from complementary members of the groupconsisting of hydrophilic polymers, hydrophobic polymers,hydrophobically modified hydrophilic polymers and hydrophilicallymodified hydrophobic polymers, such as alginates, alkyl- andhydroxyalkylcelluloses, carboxymethyl cellulose and its salts,carrageenan, cellulose and its derivatives, gelatin, gellan, guar gum,gum arabic, maleic acid copolymers, methacrylic acid copolymers, methylvinyl ether/maleic anhydride copolymers, pectins, polyacrylamide,poly(acrylic acid) and its salts, poly(ethylene glycol), poly(ethyleneimine), poly(ethylene oxide), poly(propylene oxide) poly(methacrylicacid), polystyrene and sulphonated polystyrene, poly(vinyl acetate),poly(vinyl alcohol), poly(vinyl amine), poly(vinyl pyrrolidone),polyvinyl sulphonic acid), starches and their derivatives, styrenemaleic anhydride copolymers, crotonic acid copolymers, xanthan gum orthe like, and the derivatives and copolymers thereof.

The polymers used may be pre-treated, for example by deprotonation orpreprotonation thereof, or by chemical modification thereof or the like,to tailor the type and the extent of the interpolymer interactionsacting to form the interpolymer complex.

The polymers used may be linear, branched, star-shaped, comb-shaped,cross-linked, grafted, or the like.

The active substances which may be encapsulated in the interpolymercomplexes to form the encapsulated products of the invention may includeliving organisms such as bacteria, prebiotics, probiotics, spermatozoa,ova, embryos, cells, blastocysts or the like; vaccines; proteins;hormones; enzymes; pharmaceutical compositions; drugs; vitamins;minerals; trace elements; nutrients; micro-nutrients; antioxidants;radical scavengers; ultra-violet (UV) stabilizers; pigments; organic andinorganic substances; or the like. If desired, the active substancesmay, prior to encapsulation in the interpolymer complex, be absorbed oradsorbed in particles of porous inert solids, such as colloidal silica,carbon or the like.

As employed in this specification, supercritical fluid is a dense gaswhich is maintained at a temperature above its critical temperature (thecritical temperature being the temperature above which it cannot beliquefied by the application of pressure alone), and at a pressure aboveits critical pressure (the critical pressure being the pressure requiredto liquefy the gas at its critical temperature). A supercritical fluidsolvent may include one or more members selected from the groupconsisting of hydrocarbons (such as ethane, ethene, propane, pentane,cyclohexane or toluene), dimethylether, methanol, ethanol,fluorocarbons, carbon dioxide, nitrous oxide, ammonia or the like, andmixtures thereof, optionally containing one or more solubilizers, butwill usually be carbon dioxide.

It will be apparent from the aforegoing that a number of particularversions of the method of the patent invention are feasible. Thus, asforeshadowed above, and when optionally using carbon dioxide (which isthe preferred supercritical fluid) as the supercritical fluid, thesituation can arise when the active substance is insoluble in thesupercritical fluid, the complementary polymers are soluble in thesupercritical fluid, and the interpolymer complex is insoluble in thesupercritical fluid. In this case, the polymers can separately bedissolved in supercritical carbon dioxide to form complementarysolutions, after which the complementary solutions are mixed together toform a mixture and to allow the polymers to interact to form theinterpolymer complex. This interpolymer complex will automaticallyprecipitate from the supercritical fluid. Provided the active substanceis dispersed in solid particle form in the mixture from which theinterpolymer complex precipitates, the interpolymer complex willprecipitate on the particles to encapsulate them. The dispersal of theactive substance can take place in one or more of the complementarysolutions before the mixing thereof, or in the mixture, after the mixingthereof but before the precipitation of the interpolymer complex.

Instead, the complementary polymers and the interpolymer complex may allbe soluble in the supercritical fluid which is once again optionallycarbon dioxide. In this case, after separate, dissolving of the polymersin supercritical carbon dioxide to form the complementary solutions, thecomplementary solutions may be intimately mixed and then immediatelyatomized, under conditions of pressure and temperature at which thecarbon dioxide is no longer supercritical, to cause evaporation of thecarbon dioxide and precipitation of the interpolymer complex and anyremaining amounts of the complementary polymers. In this case, theactive substance can be either soluble or insoluble in the supercriticalfluid, and may be mixed into one or more of the complementary solutions,or into the mixture of the complementary solutions, before theatomizing. If it is soluble in the supercritical fluid, particlesthereof will precipitate during the atomizing and will be encapsulatedby the interpolymer complex which precipitates. Naturally, if the activesubstance is insoluble, the interpolymer complex can simply precipitatedirectly on particles thereof, in response to the atomizing. Even if theinterpolymer complex is sparingly soluble or arguably insoluble in thesupercritical fluid, atomizing may be through a nozzle into a particlecollection chamber, after rapidly mixing the complementary solutions ina mixing chamber. By atomizing immediately after the complementarysolutions are mixed is meant that the atomizing must take place beforethe interaction between the complementary polymers has advanced to astage when precipitation of the atomized mixture is ineffective toencapsulate the active substance. The carbon dioxide will be maintainedin a supercritical state until the atomization takes place, e.g. byheating thereof under pressure, and the atomizing should take place, asindicated above, while the interaction of the complementary polymers toform the interpolymer complex is still sufficiently incomplete to allowthe interpolymer complex precipitating from the atomizing mixture toencapsulate particles of the active substance therein.

A further possibility, again when using carbon dioxide in particular asthe supercritical fluid, is that the active substance is insoluble inthe supercritical carbon dioxide, while the complementary polymers areinsoluble therein, but are liquefiable or plasticisable by dissolutiontherein of the supercritical carbon dioxide, and the interpolymercomplex is similarly insoluble in the supercritical carbon dioxide butis liquefiable or plasticisable by dissolution therein of thesupercritical carbon dioxide. In this case a dry blend of the activematerial and the complementary polymers, all in sufficiently finelydivided particulate form, e.g. smaller than 1000 μm, preferably smallerthan 500 μm, and more preferably smaller than 300 μm, can be made, theblend being exposed to supercritical carbon dioxide to liquefy orplasticise the polymers by dissolving therein, to cause or allow them tointeract together to form the interpolymer complex, which complexbecomes and/or remains liquefied or plasticised by carbon dioxidedissolved or dissolving therein, the liquefied polymers and interpolymercomplex typically having viscosities such that the active substance isheld in suspension. The suspension of active substance in liquefied orplasticised interpolymer complex can then be atomized, e.g. by means ofa spray nozzle into a particle collection chamber, into an atmosphere ata temperature and pressure selected so that the supercritical carbondioxide dissolved in the atomized interpolymer complex evaporates toleave particles of the active substance encapsulated by the interpolymercomplex. If, instead, one or more of the complementary polymers is notliquefiable or plasticisable, but the interpolymer complex isliquefiable or plasticisable, a variation of this method can be used,provided that the complementary polymers are sufficiently intimately,blended in sufficiently finely divided form to interact together to formthe interpolymer complex. Indeed, the method can in principle also beused even if the active substance is soluble in the supercritical carbondioxide and/or in the complementary polymers or interpolymer complex, asit will precipitate and become encapsulated in the interpolymer complexduring the atomization. Methods involving atomization of liquefied orplasticised interpolymer complex are expected to have the advantage ofefficient use of pressure chamber volume, in which the supercriticalcarbon dioxide is contained, when mixed with the active substance, withthe complementary polymers and/or with the interpolymer complex, as itcan lead to the production of atomizable mixtures containing far higherconcentrations of interpolymer complex and of complementary polymers inone or more of which the supercritical carbon dioxide is dissolved, thanwhen the complementary polymers or the interpolymer complex have to bedissolved in the supercritical fluid. Naturally, for this particularmethod, a suitable particulate pre-prepared interpolymer complex can beused instead of starting with the complementary polymers, thepre-prepared interpolymer complex being blended with active substance,which is typically particulate, before, during or after the liquefyingor plasticising of the interpolymer complex, whether or not the activesubstance is soluble in the supercritical carbon dioxide.

A still further possibility is when an above blend is too viscous toatomize, e.g. because the interpolymer complex formed is insoluble inand not liquefiable or plasticisable by the supercritical carbondioxide, the complementary polymers however being insoluble in, butliquefiable or plasticisable by, the supercritical carbon dioxide, andthe active substance being either soluble or insoluble in thesupercritical carbon dioxide in the polymers and/or in the complex. Inthis case, after the complementary polymers have interacted to form theinterpolymer complex, if a pre-prepared interpolymer complex is not usedinstead, the liquefied or plasticised interpolymer complex, blended withthe active substance, can have the pressure and temperature of itsenvironment reduced sufficiently to allow evaporation of thesupercritical carbon dioxide, to leave a solid residue of interpolymercomplex with active substance dispersed therein, which can be subjectedto size reduction, e.g. by milling, to produce the active substanceencapsulated in the interpolymer complex as a product.

A still further possibility for the method, when the interpolymercomplex is insoluble in the supercritical fluid such as carbon dioxide,if for the particulate complementary polymers to be liquefied orplasticised separately with supercritical carbon dioxide, thecomplementary polymers then being mixed and atomized, e.g by injectingthem into a mixing chamber leading through a spray nozzle to acollecting chamber, interaction of the polymers to form the interpolymercomplex taking place before evaporation of the carbon dioxide.Naturally, the atomization will take place at a temperature and pressureat which the carbon dioxide is not supercritical. While this version ofthe method can be used in principle whether the active substance issoluble or insoluble in supercritical carbon dioxide, being dissolved inone or more of the complementary polymers before or after they areliquefied or plasticised, or indeed being mixed in said particulate formwith them during the mixing thereof, and while this version of themethod can be used, whether or not the interpolymer complex isliquefiable or plasticisable by supercritical carbon dioxide dissolvedtherein, this method is expected to be particularly useful if the activesubstance is insoluble in the supercritical carbon dioxide, and theinterpolymer complex is insoluble therein and not liquefiable thereby.

In versions of the method, when a solid residue comprising activesubstance dispersed in interpolymer complex is milled to obtain theparticulate product, some of the active substance may be exposed at theparticle surfaces by the milling, so that the active substance is notentirely encapsulated. It is expected, however, that the proportionateactive substance so exposed will be negligible, compared with theproportion of active substance in the product which is indeed fullyencapsulated by the interpolymer complex.

As far as process parameters are concerned, these will depend on theversion of the above method used, and on the supercritical fluid usedand its critical temperature and critical pressure, andsuitable/acceptable or optimum parameters should be determined byroutine experimentation, bearing practical and economic considerationsin mind.

As indicated above, carbon dioxide is expected to be the usualsupercritical fluid of choice, by virtue of its low cost, environmentalacceptability, and ready availability, and by virtue of its acceptablecritical temperature and critical pressure. For carbon dioxide it isexpected that the method will usually be carried out at a pressure above75 bar (1 bar is 100 kPa or 100 000 N/m², being 1.01324 atmospheres),preferably 150-500 bar and more preferably 250-400 bar. As far astemperature is concerned, the carbon dioxide will be at a temperatureabove the 32° C. critical temperature, for example 32-150° C.,preferably 32-100° C. and more preferably 32-50° C.

For carbon dioxide in particular, but also for other supercriticalfluids, the solids content of the starting mixture excluding the supercritical fluid may be 0.1-80% by volume, preferably 10-70% and morepreferably 20-60%, i.e. based on reactor volume. Any entraining agentsused may in total form 0.01-10% by mass, preferably 0.1-5% and morepreferably 0.5-2%, of the total mass of the entraining agent and thecarbon dioxide supercritical fluid in the starting mixture loaded intothe reactor, with similar proportions expected to be suitable for othersupercritical fluids or mixtures thereof. Any viscosity-reducing agentused may form 1-90% by mass, preferably 5-70% and more preferably10-60%, of the total mass of the active substance, the complementarypolymers or pre-prepared interpolymer complexes, and theviscosity-reducing agents in the starting mixture loaded into thereactor. Similarly, any polymeric surfactants used may form 1-90% bymass, preferably 5-70% and more preferably 10-60%, of the total mass ofthe active substance, the complementary polymers or pre-preparedinterpolymer complexes, and the polymeric surfactants in the startingmixture loaded into the reactor. Also similarly, any solubilising agentsused may form 1-90% by mass, preferably 5-70% and more preferably10-60%, of the total mass of the active substances, the complementarypolymers or pre-prepared interpolymer complexes, and the solubilisingagents in the starting mixture loaded into the reactor. The activesubstance content may in turn amount to 0.01-60% by mass, preferably 0.1-50% and more preferably 1-40%, of the total mass of theactive-substances and the complementary polymers or pre-preparedinterpolymer complexes in the starting mixture loaded into the reactor.

When two complementary polymers are used, the mass ratio therebetweenwill depend on the nature or identity of the complementary polymersused, and on the interaction between them to form the interpolymercomplex, and this mass ratio is expected to be 0.5:99.5-99.5:0.5, moreusually 1:99-99:1 and typically 10:99-90:10. In other words (and thesame applies when three or more complementary polymers are used), eachcomplementary polymer may make up at least 0.5% by mass of the totalmass of the complementary polymers used, preferably at least 1 % andmore preferably at least 10%; and, similarly, each said complementarypolymer will make up at most 99.5% of the total mass of thecomplementary polymers used, preferably at most 99% and typically atmost 90%.

The invention will now be described, by way of non-limitingillustration, with reference to the following Examples and to theaccompanying diagrammatic drawings, in which:

FIGS. 1-3 show, in schematic sectional side-elevation, a high pressurereactor during use thereof in accordance with the method of the presentinvention;

FIGS. 4-6 show, in similar schematic sectional side-elevation, amodification of the reactor of FIGS. 1-3, also during use thereof, inaccordance with the method of the present invention;

FIGS. 7-9 show, again in schematic sectional side-elevation, anotherhigh pressure reactor during use thereof in accordance with the presentinvention;

FIG. 10 shows plots of Fourier Transform infra-red spectra, respectivelyof two complementary polymers and of an interpolymer complex formed byinteraction therebetween, in which transmittance as a percentagerelative to background is plotted against wavenumber in cm⁻¹; and

FIG. 11 shows a plot of percentage release against time of the releaseof an active substance encapsulated in accordance with the method of thepresent invention, in aqueous liquids at different pH's.

In FIGS. 1-3 of the drawings, reference numeral 10 generally designatesa high-pressure reactor for carrying out the method of the presentinvention. The reactor 10 comprises a housing 12 provided with a closure14. The housing has a hollow interior 16, divided by a movable partition18 into a pair of pressure chambers 20, 22, each provided with apropeller-type stirrer 24. The chambers 20, 22 and the housing 12 arecircular in cross-section, the housing 12 being axially elongated withthe chambers 20, 22 co-axially and horizontally aligned with each other.The chamber 22 has a slightly larger diameter than that of the chamber20, and the closure 14 is a lid at the end of the chamber 22 remote fromthe chamber 20. The partition 18 is a circular disc having a chamferededge which seats sealingly against an internally tapered part of thewall of the housing 12, said tapered part interconnecting the chambers20, 22. The partition 18 is axially movable between a closed position(FIGS. 1 and 2) in which it isolates the chambers 20, 22, and seals themoff, from each other, and an open position (FIG. 3) in which it permitscommunication, and fluid flow, therebetween. The chambers 20, 22 areshown containing supercritical carbon dioxide fluid. In FIG. 1, a layer26 of particles is shown on the lower surface of the interiors of thechambers 20-22, below supernatant supercritical carbon dioxide at 28. InFIGS. 2 and 3 particles from the layers 26 are shown dispersed andsuspended in the carbon dioxide 28.

Turning to FIGS. 4-6, the same reference numerals are used to designateto the same parts as in FIGS. 1-3 unless otherwise specified. Theprincipal difference between FIGS. 4-6 on the one hand, and FIGS. 1-3 onthe other hand, is that the lower surfaces of the interiors of thechambers 20, 22 in FIGS. 4-6 are provided with fluid outlets 30 whichare in turn provided with respective shut-off valves 32. The outlets 28lead into a conduit 34 which in turn leads to a particle collectionchamber defined in the hollow interior of a housing 36, into which theconduit 34 feeds via a spray-nozzle 38. No suspended particles are shownin the chambers 20, 22 of FIGS. 3 and 4, and in FIG. 4 dried and dryingparticles are shown in the form of a spray in the chamber 36, arisingfrom atomized supercritical carbon dioxide entering chamber 36 via thenozzle 38 leading from the conduit 34.

In FIGS. 7-9 a reactor generally designated 40, is shown comprising anelongated rectangular hollow housing 42 defining a single pressurechamber 44. The chamber 44 is shown containing a propeller-type stirrer46. In FIG. 7 a layer of particles is shown at 48 on a floor 50 of thechamber 44, and in FIGS. 8 and 9 a layer 52 of liquefied or plasticisedparticles is shown on said floor 50. The chamber 44 is shown having afloor-level outlet 54 through an end wall 56 of the housing 42. Theoutlet 54 leads through a shut-off valve 58 to a spray nozzle 60discharging into a hollow housing 62 having an interior defining aparticle collection chamber. In FIG. 9 dried and drying particles areshown in the chamber 62 arising from atomized liquefied or plasticisedparticles from the layer 52 sprayed into the chamber 62 via the nozzle60.

In FIG. 10 are plotted three Fourier Transform spectra, respectivelydesignated A, B, C. Spectrum A is for a complementary polymer which is apoly(vinyl acetate)-crotonic acid copolymer, spectrum C being for acomplementary polymer which is a poly(vinyl pyrrolidone), and spectrum Bbeing for the interpolymer complex product of interaction between thesaid complementary polymers.

In FIG. 11 is shown a plot of the release of the active substance inquestion at a pH of 6.8, designated D and a plot of the release of theactive substance at a pH of 1.2, designated E.

EXAMPLE 1 Interpolymer Complex Formation—Poly(vinylacetate)-CrotonicAcid Copolymer and Poly(vinyl Pyrrolidone)

In this example, complementary polymers in the form of 0.4 grams ofpoly(vinyl acetate)-crotonic acid copolymer (PVAc-CA; Aldrich) wereweighed off and physically blended with 3.6 grams of poly(vinylpyrrolidone) (PVP—Kollidon 12PF, BASF). The powder blend obtained wasplaced in a reactor (for example reactor 40 of FIGS. 7-9) and thereactor was sealed. The reactor was flushed with carbon dioxide for oneminute.

The reactor was then pressurised with carbon dioxide from atmospheric upto a pressure of 400 bar and the temperature was raised from ambient upto 35° C. to create the desired supercritical conditions in the reactor.The blend was stirred at 2000 rpm for 2 hours to liquefy and plasticisethe complementary polymers and to dissolve carbon dioxide therein. Thepressure was then decreased to atmospheric pressure and the reactionproduct removed from the reactor. The product was found to be amonolithic piece of foamed elastic interpolymer complex. Scanningelectron microscope photomicrography of the product showed it tocomprise a single continuous phase. FTIR (Fourier Transform Infrared)spectroscopic measurements were carried out on the product interpolymercomplex and on both the starting complementary polymers (PVP andPVAc-CA). FIG. 10 shows the respective spectra of the complementarypolymers (spectra A and C) and the product interpolymer complex(spectrum B).

The PVP had a carbonyl absorption band at 1654 cm⁻¹ (spectrum C). ThePVAc-CA had an acetate absorption band overlapping with two carbonylstretching modes of the free and self-associated carboxylic acid groups(Zhou et al., 1998 XPS and FTi.r. Studies of Interactions inpoly(carboxylic acid)/Poly(vinyl-pyridine) Complexes—Polymer 39(16)3631-3640). This resulted in the appearance of a broad absorption bandfrom 1700 to 1800 cm⁻¹ (spectrum A). This broad absorption band narrowedsharply for the product interpolymer complex (spectrum B). The PVPcarbonyl absorption band at 1654 cm⁻¹ (spectrum C) was shifted to 1671cm⁻¹ for the product interpolymer complex (spectrum B). These changesare both indications of interaction between the carboxylic acid group ofthe PVAc-CA and the carbonyl group of the PVP, and are characteristic ofinterpolymer complexes where hydrogen bonding occurs (Zhou et al., 1998,supra).

The physical characteristics of the product polymer also indicated thatan interpolymer complex had been formed. First, the product polymer waselastic and tough, while both of the complementary polymers werebrittle. Secondly, while PVP is highly hygroscopic, the product polymerdisplayed no evident hygroscopicity. Visual inspection of a physicalblend of the PVP and PVAc-CA and of the product interpolymer complexafter exposure to the atmosphere for 24 hours showed that the physicalblend had clearly picked up moisture while the product polymer had not.

EXAMPLE 2 Interpolymer Complex Formation—PVAc-Ca and PVP withPoly(ethyleneglycol) as Viscosity Modifier

In this Example, Example 1 repeated except that 1.8 grams of poly(vinylacetate)-crotonic acid copolymer (PVAc-CA, Aldrich) were weighed off andphysically blended with 16.2 grams of poly(vinyl pyrrolidone)(PVP—Kollidon 12PF, BASF) and with 2 grams of poly(ethylene glycol) (PEG1000, Merck), as viscosity modifier. The powder blend obtained wasplaced in the reactor (See 40 in FIGS. 7-9) and the reactor sealed. Thereactor was flushed with carbon dioxide for one minute.

The reactor was then pressurised with carbon dioxide from atmospheric upto a pressure of 400 bar and the temperature was increased from ambientto 35° C. to create the desired supercritical conditions in the reactor.The blend was stirred at 2000 rpm for 2 hours. The pressure was thendecreased to atmospheric pressure and the reactor opened. Aninterpolymer complex was found to have been formed in the reactor. Theviscosity of the complex was found to be lower than that of the complexformed without PEG (See example 1), as indicated by the foam structureand foam distribution in the reaction chamber 44 of the reactor. Thefoam consisted of a single continuous phase, indicating good miscibilitybetween the PEG, PVP and PVAc-CA.

When the interpolymer complex was sprayed through a nozzle (See 60 inFIGS. 7-9) at 275 bar, particles were formed from which a film-formingtendency of the complex was clearly discernible, as were structuresformed by the rapid escape of the carbon dioxide from solution in thecomplex.

EXAMPLE 3 Interpolymer Complex Formation—PVP-PVAc and Poly(vinylpyrrolidone)-Poly(vinyl acetate) Copolymer

In this Example the procedures of Examples 1 and 2 were repeated exceptthat 0.4 grams of poly(vinyl acetate)-crotonic acid copolymer (PVAc-CA,Aldrich) were weighed off and physically blended with 3.6 grams ofpoly(vinyl pyrrolidone)-poly(vinylacetate) copolymer (PVP-PVAc—PVP-VAS630, ISP). The blend was placed in the reactor and the reactor sealed.The reactor was flushed with carbon dioxide for one minute.

The reactor was then pressurised with carbon dioxide from atmospheric upto a pressure of 400 bar and the temperature was increased from ambientto 35° C. to create the desired supercritical conditions in the reactor.The blend was stirred at 2000 rpm for 2 hours. The pressure was thendecreased to atmospheric pressure and the reactor opened. Aninterpolymer complex was found to have been formed in the reactor.

EXAMPLE 4 Interpolymer Complex Formation—PVAc-CA and Poly(ethyleneoxide)-Poly(propylene oxide)-Poly(ethylene oxide) Tri-Block Copolymer

In this Example the procedures of Examples 1-3 were repeated except that0.4 grams of poly(vinyl acetate-crotonic acid copolymer (PVAc-CA,Aldrich) were weighed off and physically blended with 3.6 grams ofpoly(ethylene oxide)-poly(propylene-oxide)-poly(ethylene oxide)tri-block copolymer (PEO-PPO-PEO-Pluronic PE6800 BASF). The powder blendobtained was placed in the reactor and the -reactor sealed. The reactorwas flushed with carbon dioxide for one minute.

The reactor was then pressurised with carbon dioxide from atmospheric upto a pressure of 400 bar and the temperature was increased from ambientup to 35° C. to create the desired supercritical conditions in thereactor. The blend was stirred at 2000 rpm; for 2 hours. The pressurewas then decreased to atmospheric pressure and the reactor opened. Aninterpolymer complex was found to have been formed in the reactor.

EXAMPLE 5 Encapsulation of Insoluble Drug (Indomethacin)

In this example the following powder ingredients were physicallyblended:

Ingredient Trade Name Supplier Amount poly(vinyl Kollidon 12 PF BASF 7.2g pyrrolidone) poly(vinyl acetate)- — Aldrich 0.8 g crotonic acidIndomethacin Indomethacin Sigma   2 gA powder blend was obtained with a maximum particle size of 500 μm,which powder blend was placed in the reactor (See 40 in FIGS. 7-9) andthe reactor sealed. The reactor was flushed with carbon dioxide for oneminute.

The reactor was then pressurised with carbon dioxide from atmospheric upto a pressure of 400 bar and the temperature was increased from ambientup to 35° C. to create the desired supercritical conditions in thereactor. The blend was stirred at 2000 rpm for 2 hours. The pressure wasthen decreased to atmospheric pressure and the reactor opened.

An interpolymer complex containing therein dispersed particles of theIndomethacin was found to have been formed in the reactor. It wasremoved from the reactor. The complex was then milled in a coffeegrinder for 5 minutes to reduce particle size to at most about 50 μm. 2%by mass pharmaceutical grade particulate magnesium stearate(FACI,Petrow) was admixed with the milled complex as a binder. Themixture was then similarly milled for another 2 minutes to achieveuniform dispersion in the complex of the binder of similar particlesize.

6 mm tablets were then pressed from the complex/binder mixture using aManesty Type F3 Tablet Press. The tablets were used for dissolutiontests in a Hanson SR-8 Dissolution Test Station. Dissolution tests werecarried out at 37° C. and with stirrer speed of 75 rpm.

Determination of the Indomethacin release rate was done using UVspectrophotometry. FIG. 11 shows results of dissolution tests carriedout respectively at a pH of 6.8 and at a pH of 1.2. The results arecomposite (average) results from eight experiments.

FIG. 11 shows controlled release of encapsulated Indomethacin drug fromthe tablets produced. Controlled release of the drug was achieved at apH of 6.8, while almost no drug was released at a pH of 1.2.

EXAMPLE 6 Formation of Interpolymer Complex Before Liquefaction

In this Example 10 grams of poly(vinyl acetate)-crotonic acidcopolymer(PVAc-CA, Aldrich) were weighed off and dissolved in 90 gramsof ethanol heated to 50° C. Then 10 grams of poly(vinyl pyrrolidone)(PVP-Kollidon 12PF, BASF) were dissolved in 90 grams of ethanol. The twopolymer solutions in ethanol were then mixed together. The ethanol wasthen evaporated from the mixture by heating in a vacuum oven at atemperature of about 60° C. and at a reduced absolute pressure of about10 kPa, to obtain a solid interpolymer complex residue. This residue wasthen milled in a coffee grinder for 5 minutes to reduce its particlesize to at most 50 μm.

Then 8 grams of the milled complex so obtained was physically blendedwith 2 grams of Indomethacin and further processed as described inExample 5. A similar product to that of Example 5 was obtained.

EXAMPLE 7 Addition of Polymeric Surfactant to Improve Liquefaction

The following ingredients were physically blended:

Ingredient Trade Name Supplier Amount Poly(vinyl Kollidon 12 PF BASF 7.2g pyrrolidone) Poly(vinyl acetate)- — Aldrich 0.8 g crotonic acidPEO-PPO-PEO Pluronic PE6800 BASF   2 g copolymerThe blending acted to produce a powder blend having a maximum particlesize of 500 μm, which powder blend was placed in a reactor (40 in FIGS.7-9) and the reactor was sealed. The reactor was then flushed withcarbon dioxide for one minute.

The reactor was then pressurised with carbon dioxide from atmospheric upto a pressure of 275 bar and the temperature was increased from ambientup to 35° C., to create the desired supercritical conditions in thereactor. The blend was stirred at 2000 rpm by the stirrer to achieveliquefaction of the blend.

The liquefied blend was sprayed at a pressure of 275 bar through a 0.13mm orifice in a spray nozzle into a collection chamber. A dryparticulate product, consisting of a homogeneous blend of theinterpolymer complex and the polymer surfactant, was obtained.

The full names and addresses of the suppliers of the starting materialsused in the, examples are as follows:

Aldrich Aldrich Chemical Company Post Office Box 355 Milwaukee Wisconsin53233 USA BASF BASF South Africa (Proprietary) Limited Post Office Box2801 Halfway House 1685 South Africa Merck Merck (Proprietary) LimitedPost Office Box 2805 Durban 4000 South Africa ISP ISP Europe 40 AlanTuring Road Surrey Research Park Guildford Surrey GU2 5YF England SigmaSigma (Proprietary) Limited PO Box 4853 Atlasville 1465 South AfricaPetrow CJ Petrow Chemicals (Proprietary) Limited (Agents) 68 5^(th)Avenue Albertville 2193 South Africa

1. A method of encapsulating an active substance in a polymericencapsulating material to make an encapsulated product in particulateform, the method comprising the steps of: forming a mixture of asupercritical fluid, a polymeric encapsulating material, and an activesubstance; causing or allowing the encapsulating material to encapsulatethe active substance to form an encapsulated product; separating theencapsulated product from the supercritical fluid to obtain encapsulatedproduct particles in which the active substance is encapsulated by theencapsulating material; wherein the supercritical fluid is carbondioxide; wherein the encapsulated product comprises the active substancethat has been encapsulated by an interpolymer complex; wherein at leasttwo different complementary polymers of different species interacttogether by hydrogen bonding to form the interpolymer complex; whereinthe forming of the mixture comprises the step of dissolving thesupercritical fluid in the interpolymer complex to liquefy or plasticizethe interpolymer complex; and wherein the polymers which form theinterpolymer complex are selected from complementary members of thegroup consisting of poly(vinyl acetate)-crotonic acid copolymer,poly(vinyl pyrrolidone), poly(ethylene glycol), poly(vinylpyrrolidone)-poly(vinyl acetate) copolymer and poly(ethyleneoxide)-poly(propylene oxide)-poly(ethylene oxide)triblock copolymer. 2.A method as claimed in claim 1, in which the forming of the mixturecomprises the steps of blending at least two complementary polymers,capable of interacting together when blended and in liquefied orplasticized form, to obtain a blend comprising the polymers, dissolvingthe supercritical fluid in the polymers, and causing or allowing thepolymers to interact together in blended liquefied or plasticized formto form the interpolymer complex.
 3. A method as claimed in claim 2, inwhich the blending of the polymers is to form a particle blendcomprising polymer particles having a particle size of at most 1000μm,after which the supercritical fluid is dissolved in the polymerparticles.
 4. A method as claimed in claim 2, in which the supercriticalfluid is separately dissolved in the complementary polymers in particleform comprising particles having a particle size of at most 1000 μm,after which the polymers in liquefied or plasticized form are blended toform the blend.
 5. A method as claimed in claim 1, in which causing orallowing of the interpolymer complex to encapsulate the active substancecomprises atomizing the mixture in an atmosphere having a temperatureand pressure such that the supercritical fluid evaporates to leave aresidue comprising particles in which the active substance isencapsulated by the interpolymer complex.
 6. A method as claimed inclaim 5, in which the dissolving of the supercritical fluid in theinterpolymer complex to liquefy or plasticize the interpolymer complexincludes the step of dispersing a viscosity-reducing agent in theinterpolymer complex to reduce the viscosity of the interpolymer complexto facilitate the atomizing.
 7. A method as claimed in claim 1, in whichthe causing or allowing of the interpolymer complex to encapsulate theactive substance comprises allowing the supercritical fluid to evaporateto leave a solid residue comprising the active substance dispersed inthe interpolymer complex, and subjecting the residue to size reductionto obtain particles in which the active substance is encapsulated by theinterpolymer complex.
 8. A method as claimed in claim 1, in which theforming of the mixture includes the step of admixing a polymericsurfactant into the mixture.
 9. A method as claimed in claim 1, whichincludes subjecting the encapsulated product to size reduction to obtainencapsulated product particles.
 10. A method as claimed in claim 1, inwhich the forming of the mixture is in the absence of a liquid.